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8th December 2010 @ 03:39
10g-scale racemic resolution of rac-PZQamine

scheme MW49-5.png


See related experiments:
Optimizing the racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-14)
Scale-up: Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-12)
Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-5 - MW49-11)
Racemic resolution of praziquanamine with (+)-Dibenzoyl-D-tartaric acid (MW49)
Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30) -> S-(+)-PZQamine
Diastereomeric salt resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid obtainig S-(+)-PZQamine (MW47-3)

Start time: 3:15 PM 8/12/2010
End time: 6:15 PM 8/12/2010

Procedure:
rac-Praziquanamine (10.0 g, 49.5 mmol, M.W. 202.1 g/mol) and (-)-dibenzoyl-L-tartaric acid* 2 i-PrOH (23.7 g, 49.5 mmol, M.W. 478.5 g/mol) were dissolved in a mixture of i-PrOH (450 mL) and water (90 mL) by heating the stirred mixture (yellow solution from impurities of the PZQamine (decomposition under irradiation/light)).
To accelerate the cooling process, the solution was placed in a water bath on room temperature (fast formation of nice crystals). After 2 h the crystalline precipitate was filtered of and dried.
The mother liquor was placed in the fridge overnight (5°C), but only a few more crystals precipitated. (almost fully precipitated)
-> right concentration of the solution, maybe could be a bit more concentrated to obtain a yield around 50%

Yield of the diasteromeric salt: 12.1 g (21.6 mmol, 44%) of a pale yellow crystalline solid
[M.W. diastereomeric salt = 560.6 g/mol]
m.p.=143-145°C

Mother liquor: Solvent was evaporated and solid residue was dried under high vac.
diastereomeric salt: 15.9 g (28.4 mmol, 57%) of a pale yellow solid

-> right concentration of the solution, maybe could be a bit more concentrated to obtain a yield around 50%

2. Crystallization:
The salt (12.1 g, 21.6 mmol) was dissolved in a mixture of i-PrOH (180 mL) and water (90 mL) by heating. After 2 h the crystalline precipitate was filtered off.
Yield of the diasteromeric salt: 9.54 g (17.0 mmol, 79%, 34% overall yield) of a colorless crystalline solid
m.p.=143.5-145.5°C
mother liquor stored in the fridge over 3 days, obtained crystals were filtered off: yield 703 mg (1.25 mmol, 6%, 3% overall yield) - combined with the first precipitaton
-> Summary of the 2. crystallization: 10.2 g (18.3 mmol, 85%, 37% overall yield)

Liberation:
To the diatereomeric salt (10.4 g) was added 100 mL of water and the stirred suspension was carefully made basic to pH 11 by adding 2 N NaOH solution. When the salt was completely dissolved the solution was extracted with DCM (4 x 15 mL). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure.

- same procedure for the combined mother liquors after the solvents was evaporated

To combined basic aq. solution was added i-PrOH (5 mL) and the solution was made acidic to pH 1-2 by adding 2 N HCl. The precipitate was filtered off and dried in vacuum.

Results:
Resolved (-)-PZQamine: 3.32 g (33% overall yield, 16.4 mmol) as a colorless solid
m.p. 122-123°C
[α]D20 = -305° (c=1, DCM)
1H NMR: Data: 1H NMR MW49-13 (-)-PZQamine.pdf
-> ee = 97% (determined by chiral HPLC from the (R)-PZQ derivative)

Recovered PZQamine from the mother liquor (crude): 5.34 g (53%, 26.4 mmol) as a yellow solid
m.p. 102-104°C
[α]D20 = +170° (c=1, DCM)
1H NMR: Data: 1H NMR MW49-13 Remaining PZQamine.pdf

Recovered (-)-dibenzoyl-L-tartaric acid* 2 i-PrOH[/url] (crude):
21.1 g (89%, 44.1 mmol)
m.p. 108-110°C
1H NMR: Data: 1H NMR MW49-13 Resolving agent.pdf
Data: 1H NMR MW49-13 recovered resolving agent (recrystallized).pdf

See subsequent experiment: N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine in a multigram scale (MW48-4)


References:
[1] "Novel processes for the preparation or (R)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol", Daugs et al. US Patent Application (2002), US 2002/0151717A1. [Example 20, p. 27-28]
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7th December 2010 @ 05:20
Conversion of enantiopure R-(-)-Praziquanamine (PZQamine), obtained from the Scale-up: Racemic resolution of praziquanamine with (-)-Dibenzoyl-L-tartaric acid (MW49-12), to R-(-)-PZQ in order to determine the ee by chiral HPLC

See also:
From R-(-)-Praziquanamine to R-(-)-Praziquantel (MW48-1): N-Cyclohexanoyl-protection of the enantiopure PZQamine
From S-(+)-Praziquanamine to S-(+)-Praziquantel (MW48-2): N-Cyclohexanoyl-protection of the enantiopure PZQamine
N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine in a multigram scale (MW48-4)
N-Cyclohexanoyl-protection of the enantiopure R-(-)-PZQamine to PZQ (MW48-5)

Scheme R-PZQamine MW48-1


Hazard and Risk Assessment:
HIRAC MW48


Start time: 4:30 PM 7/12/2010
End time: 8:40 PM 7/12/2010


To a cooled solution of S-(+)Praziquanamine (150 mg, 743 µmol; M.W. = 202.3 g/mol) in DCM (5 mL) at 0°C was added triethylamine (112 mg, 155 µL, 1.11 mmol, 1.5 eq.; M.W.=101 g/mol, density=0.726g/mL) and cyclohexanoyl chloride (120 mg, 109 µL, 817 µmol, 1.1 eq.; M.W.=147 g/mol, density=1.096g/mL). The solution was stirred for 4 h at room temperature.
Work-up:
- quenched with water and stirred for further 15 min
- extracted with DCM, washed the organic layer with 1 N HCl solution
- column chromatography (EA, hexane = 1:1)

Yield: 228 mg (730 µmol, 98%) of a sticky solid (remaining solvent)
[M.W.=312.4 g/mol]
[α]D20 = -127° (c=1, EtOH)
(lit. [1] [α]D20 = 126.9 (c = 1, EtOH 99.%) [α]D20 = 135.0 (c = 1, CHCl3))
-> chiral HPLC

References:
[1] "Enantioselective synthesis of (R)-(−)-praziquantel (PZQ)", P. Roszkowski J. K. Maurin and Zbigniew Czarnocki, Tetrahedron: Asymmetry,2006, 17, 9, 15, 1415-1419. (doi:10.1016/j.tetasy.2006.04.023)

See: Optical rotation of R-(-)-PZQ and S-(+)-PZQ
2nd December 2010 @ 05:35
Scale-up of Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30)

See also:
See Synthesis of (+)-Dibenzoyl-D-tartaric acid (MW10-5)
and Synthesis of (+)-Dibenzoyl-D-tartaric acid - alternative route (MW10-6)

Reaction Scheme


Hazard and Risk Assessment:
HRAF MW10.pdf


Start time: 4:00 PM 02/12/2010
End time: 8:00 PM 02/12/2010

Procedure: [1]
A mixture L-(+)-tartaric acid (27.0 g, 180 mmol, M.W. 150.1 g/mol) and benzoyl chloride (88.6 g, 73 mL, 630 mmol; M.W. 140.6 g/mol, 1.21 g/mL) was heated to 130°C for 4 h. After which time a pale yellow solid was formed. The mixture was cooled to room temperature, washed with cold Et2O and recrystallized from toluene (400 mL).

Yield of the anhydride: 48.3 g (141 mmol, 79%) colorless, crysalline solid
[Anhydride, C18H12O7 M.W. = 340.3 g/mol]
[Dibenzoyl-tartaric acid, M.W. = 358.3 g/mol]
[Dibenzoyl-tartaric acid * 2 i-PrOH, C24H30O10 M.W. = 478.5 g/mol]

Hydrolysis of the anhydride:
Start time: 3:00 PM 03/12/2010
End time: 5:00 PM 03/12/2010

The anhydride (48.3 g, 141 mmol) was dissolved in a mixture of acetone (200 mL) and water (20 mL) and heated to reflux for 2 h. Water (200 mL) was added and aceton was removed under reduced pressure. After further addition of water (200 mL) the mixture was heated refluxed and cooled to 0°C for 30 min. The water was removed by filtration and the colorless solid residue was freeze-dried (alternative method: dissolving solid in ethyl acetate and dry over Na2SO4).

The solid was recrystallized from i-PrOH/hexane:
1. crystallization ~ 50 g from i-PrOH/hexane (~ 500 mL 1:1): yield 28.3 g (59.0 mmol, 33%)
2. crystallization 33 g from i-PrOH/hexane (~ 400 mL 1:2): yield 24.4 g (51.0 mmol, 28%), remain 8.5 g
3. crystallization (8.5 g) from i-PrOH/hexane (~ 50 mL 1:2): yield 6.22 g (13.0 mmol, 7%)

-> Yield 58.9 g (123 mmol, 68%) (-)-dibenzoyl-L-tartaric acid * 2 i-PrOH
[M.W.(C24H30O10) = 478.5 g/mol]

Analytical data:
m.p. 98-100°C (lit. 95–98°C for DBTA * H2O [3])
1H NMR (DMSO-d6, 200 MHz): δ = 1.03 (d, J=6 Hz, 12H), 3.78 (sep, J=6 Hz, 2H), 5.88 (s, 2H), 7.57-7.64 (m, 4H), 7.70-7.74 (m, 2H), 8.00-8.04 (m, 4H), 14.00 (bs, 2H). Data: 1H NMR MW10-7.pdf
13C NMR (DMSO-d6, 50.3 MHz): δ = 25.5 (4C), 62.2 (2C), 71.6 (2C), 128.6 (2C), 129.1 (4C), 129.5 (4C), 134.2 (2C), 164.8 (2C), 167.3 (2C). Data: 13C NMR MW10-6
IR (neat): nu = 3465 cm-1, 2975, 1730, 1237, 1098, 938, 706.Data: MW10-1-30 acid.pdf -> no OH-peak for i-PrOH Data: IR MW10-5.pdf
[α]D20 = -85.0° (c=1, EtOH). ([α]D20 = 119.4° (c=1.055, MeOH))
MS (ESI (-)) m/z (%): 357 (100) [M-H]-.
HRMS (ESI (-)) Calcd. for [ C18H13O8]-: 357.0616, found: 357.0616.
HRMS (ESI (+)) Calcd. for [C18H14O8+Na]+: 381.0581, found: 381.0579.
C24H30O10 (478.5 g/mol): calc. C 60.24%, H 6.32%; found: C 60.27%, H 6.33% -> dibenzoyltartaric acid * 2 i-PrOH

More spectra and data:
Synthesis of (+)-Dibenzoyl-D-tartaric acid - alternative route (MW10-6)
Synthesis of (+)-Dibenzoyl-D-tartaric acid (MW10-5)
Synthesis of (-)-Dibenzoyl-L-tartaric acid (MW10-1-30)

Results:
The procedure for the synthesis of (-)-dibenzoyl-L-tartaric acid is easy to scale-up also the purification / separation from the side product benzoic acid is not a problem. However the product couldn't be crystallized from water as (-)-dibenzoyl-L-tartaric acid monohydrate (neccessary?) therefore it was recrystallized from iso-propanol/hexane.
Yield could be improved but ordering the chemical from a chemical supplier is more economic... (AU$ 16 per kg (-)-dibenzoyl-L-tartaric acid monohydrate for an order volume of 1000 kg)


References:
[1] “The Reduction of Various Sugar Acids to Glycitols with Lithium Aluminum Hydride”, R. K. Ness, H. G. Fletcher and C. S. Hudson, J. Am. Chem Soc. 1951, 73, 10, 4759-4761.

[2] “Relative Stereoselectivity of the Reactions of (2R,3R)- and (2R,3S)-Dibenzoyloxysuccinic Anhydrides with Chiral Amines and Alcohols”, K. H. Bell, Aust. J. Chem. 1987, 40, 399-404. doi:10.1071/CH9870399.

[3] "Convenient and Inexpensive Synthesis of (1R,2R)- trans-1-Amino-6-nitroindan-2-ol", S. Kozhushkov, D. Yufit and A. de Meijere, Adv. Synth. Catal. 2005, 347, 255– 265. (for analytical data references)

[4] "Novel processes for the preparation or (R)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol", Daugs et al. US Patent Application (2002), US 2002/0151717A1. [Example 53, p. 42]
Attached Files